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Wednesday, December 31, 2014

Today is the last official day for Chief Technology Officer Ian
MacLachlan at Tekmira. While scientifically
a great loss to Tekmira, the change
marks the end of Tekmira as a technology development company and the official beginning
as a commercially focused clinical product development company. From the clinical pipeline, it is TKM-HBV,
Tekmira’s gene silencing candidate for the finite treatment of HBV infection, which
stands out as the most important, if not existential asset to be watched in
2015.

After generation 1, 2, 3, and now even 4 SNALP LNP, and 10, 100,
1000x fold improvements in the potency and therapeutic window, the time has come to stop telling us that ‘next time will be better’ after yet another
immunostimulatory setback. In both cases (TKM-ApoB, TKM-EBOLAold),
I was willing to take the bait as the company and Dr MacLachlan explained the
basis for their continued confidence with scientific authority. For TKM-EBOLA, the plausible
explanation for the immunostimulation seen in the healthy volunteer study was particle heterogeneity following resuspension of the lyophilized
liposomes (note: a lyophilized formulation was used in that case because Ebola may have to be used in areas with unreliable cold chains; other SNALP LNP products are provided as 'wet' formulations).

However, with the recent initiation of phase I studies of generations 3 and 4 formulation of TKM-HBV and the departure of Dr MacLachlan, the company seems comfortable with taking their last two shots at proving that
SNALP LNPs can enable potent gene knockdown in the absence of transient immune suppression at comfortable safety margins and with
profiles that are competitive with the emerging conjugate platforms in RNAi and
RNaseH antisense.

Although a bit under the radar for the moment, the new
studies with non-lyophilized 3rd generation TKM-Ebola Guinea should
be informative as to whether the lyophilization hypothesis holds water. As these studies should likely be of shorter
duration than the TKM-HBV phase I studies, the safety results from those
studies should be a harbinger for the safety for at least TKM-HBVgen3, if not
TKM-HBVgen4.

The changes at the company will be welcome by some investors
which might have grown tired of holding shares in a lab experiment. On the other hand, they dampen my outlook for
other liposomal delivery opportunities not only in RNAi for oncology (see today's ho-hum update on TKM-PLK1), but also in the sizzling hot fields of mRNA and
CRISPR Therapeutics.

So good luck Ian and thanks for leaving the company in good order. Yours is also a great loss to the field of RNAi Therapeutics. Hope you will come back to Nucleic Acid Therapeutics with renewed motivation.

Hello 2015

Lastly, a Happy New Year to all my readers. 2015 should be a year that will be marked by clinical RNA Therapeutics data of ever higher quality which will make it crystal clear that RNA Therapeutics has become the 3rd major drug discovery engine of the pharmaceutical industry.

Tuesday, December 23, 2014

Last week on December 17, RXi Pharmaceuticals announced (3-month) results from a phase II study of the
company’s lead candidate RXI-109, an RNAi Therapeutic for the treatment/prevention
of dermal scars.

In this lower abdominal scar revision study 1301, one side in a given patient was treated with drug on days 1, 8, and 15 following surgery (immediate group) or on days 14, 21, and 28 (delayed group), while the other side was given placebo. An assessor blinded to which side was injected with RXI-109 or placebo was then asked to tell drug from placebo.

According to the
release, the drug-treated side was (correctly) identified 54% of the time in
the delayed treatment cohort versus 24%
of the time in the immediate treatment cohort.

In the absence of further information on the identification
procedure and scoring used (e.g. it is likely 'there is no difference' was a possible answer which would somewhat undersell the results), the following interpretation seems logical: in the
delayed treatment cohort skin wounds treated with RXI-109 looked no different
than those treated with placebo. Moreover, when treatment was started soon after scar revision surgery, RXI-109 possibly did harm.

It certainly would have helped if RXi provided the VAS score as it did in the one-month update in September.

To me, this result looks like one of the worse types of biotech trial failures. If you like to talk about 'misleading', then RXi should not look further than the title of their own press release on this failed study:

'RXi Pharmaceuticals Announces Sustained Effect of RXI-109 at Three Months Post Scar Revision Surgery and the Completion of Enrollment for its Phase 2a Trial RXI-109-1301'

Two days after the clinical trial news, the company then announced that it had licensed a non-RNAi dermal compound which is currently in phase II
studies for cancer and other proliferative diseases of the skin. A proprietary formulation of small molecule ‘immuno-modulator’
diphenylcyclopropenone (DPCP), aka Samcyprone, from an obscure company
called Hapten Pharmaceuticals.

Now on to RXi’s financials...

At the end of Q3 2014, RXi had about $10M in net cash
($10.69M cash/cash equivalents minus $1M in liabilities), spending about
$2.25M a quarter. This means they presently have ~$8M in cash minus the undisclosed cash it spent on the Hapten deal. If RXi continued with RXI-109 and RNAi and if it initiated the phase II clinical studies with Samcyprone, the cash burn would
obviously increase. Let’s say to $4M per
quarter à
$8M/($4M per quarter)= 2 quarters of cash left.

...and RXII the stock

Obviously realizing that the new asset is not not solving their financial predicament, by contrast it is only worsening it, concurrent with the Hapten deal RXi entered into a new stock purchase agreement with Lincoln Park Capital ('ATM') according to which RXi Pharmaceuticals can sell
LPC newly issued shares to raise capital. The way these deals work is that LPC would get a discount on the shares and turn around and sell
to the public market to lock in the profit. This means that if
RXi really counted on such revenues to keep their PCR machines running, any substantial
rally in RXII is likely to be met with the selling of new shares.

Adding to the pressure is the fact that major shareholder
Tang Capital, holding just shy of 50% of the fully diluted share count, has
been steadily selling down its ownership in RXi. Moreover, some of the Hapten deal (incl. milestones) was/will be paid in shares and it would be reasonable to suspect that the owners of Hapten are not in it for the potential of making money with speculating in RXII shares.

If you consider a fully diluted market cap of
$70-80M, the present situation with RXI-109 and the failure for years (also under Galena) to advance the self-delivering RNAi platform, the case can be made that there are better biotech stock investments out there.

Pick your poison

For the above reasons (including financial limitations), I tweeted
last week that the move to license Samcyprone more or less amounted to RXi
Pharmaceuticals getting out of the RNAi game. In fact, the bitter irony is that RXi was
born out of parent company Galena Pharmaceuticals making exactly the same move
(marginalizing RNAi by acquiring a non-RNAi clinical asset).

So yesterday, the CEO of RXi Pharmaceuticals issued an Open Letter that, to sum it up, I was misleading the public with my conclusions
about the strategic shifts happening at the company and was thereby scaring investors into
selling their shares:

'We can only hope that investors and shareholders who read blogs, tweets and postings from third parties purporting to have an informed view on our business will also do an in depth evaluation of the background of those who write such "reports", their past contributions to the actual progress in the RNAi space, and their possible associations to competitors and other firms working in a similar space. Notwithstanding these ill-informed criticisms, we remain optimistic about the prospects of the Company and our core technology.'

At this point, a friendly piece of advice: RXi ought to label Samcyprone an 'immuno-oncology' drug which would almost sound as sexy as the VEGF compound RXi is now 'synthesizing'.

So I’m not sure what to hope for: a) that the CEO does not
understand that continuing with two phase II compounds under present
circumstances is akin to financial suicide, especially from a shareholder’s
point-of-view; or b) that he understands it and scapegoats social media,
including myself, for calling the bluff in an effort to win time.

I suspect it’s the latter and either way shareholders are unlikely to come out ahead.
After all, when he took the helm of RXi Pharmaceuticals at a time when it was fashionable to bash and ridicule RNAi, he made it clear
that he was a ‘small molecule guy’ at heart. If I may ask you Geert, what exactly were your contributions to the actual progress of RNAi Therapeutics?

Tuesday, December 16, 2014

As promised, RNAi Therapeutics fast-follower Dicerna for the
first time disclosed last night data on GalNAc-conjugated Dicer-substrate
technology. It was not much that was
shared, but a single-dose mouse ED50 value of ~2.0mg/kg (30% knockdown at
1mg/kg) suggests that similar to Alnylam, Regulus and ISIS Pharmaceuticals before, Dicerna also
has achieved clinical relevancy with GalNAc-conjugates. In other words, the data are consistent with
robust clinical knockdowns with multi-dosing at doses of 10mg/kg or less.

By comparison, the single-dose ED50s for Alnylam’s
first-generation GalNAc-siRNA ALN-TTRsc (OTS 2012 presentation) were between 1 and 5mg/kg in mice
(20-25% knockdown at 1mg/kg) and 5mg/kg in Man (phase I study).

The data, both potency-wise and the fact that it was murine
data only (not non-human primate data), however, also make it clear that
Dicerna is at least 2 years behind Alnylam. Accordingly, the company expects to file its
first GalNAc IND in 2016, though it said it already has 4 candidates cooking
for that purpose.

Due to the competitive disadvantage, it is understandable that
Dicerna is keeping its gene targets secret (e.g. the data were against an
undisclosed gene) as the primary hyperoxaluria and HBV histories have shown that
Alnylam’s strategy is to suffocate its competition by announcing competing
clinical candidates.

On the other hand, with some luck and skill, Dicerna should
be able to exploit its secrecy and build a large competitive lead in its chosen
indications given that in going after ~2 dozen indications at once, Alnylam is
spreading itself thin. The alpha-1-antitrypsin
history where Arrowhead has well overtaken Alnylam through focus supports this. Similarly, Dicerna seems to have a good working relationship with the PH1 community which is very important in the ultra-orphan drug development field.

Overall, assuming that murine GalNAc data translate into
non-human primates and humans, the promise of being able to knock down genes in
the liver subcutaneously in a clinically relevant manner is important step
forward for Dicerna which before that was without viable delivery
technology.

Other news

In last night's presentation, Dicerna also for the first time revealed non-human primate data for its lead primary hyperoxaluria program DCR-PH1 (note: investors should discount DCR-MYC). The data show a near-elimination of the HAO1 target gene at monthly doses of 0.3mg/kg and due to the cumulative efficacy, a monthly repeat dose of ~0.1mg/kg should be feasible for a solid impact on disease-causing oxalate crystal formation. Importantly, such a dose is expected to be safe, especially with the novel 'EX' strategy whereby Dicerna is adding anti-inflammatory activities in the RNAi trigger extension.

PS: from a scientific point-of-view, it shall be interesting to see data come out relating to the impact of the nucleic acid structure (e.g. length of double-strand RNA) added to a GalNAc ligand on functional delivery efficiency. Such data would be informative on the mechanism of endo-lysosomal release and guide towards further optimization of the platform (e.g. utility of positive charge, lipophilicity, stability).

Monday, December 15, 2014

Dicerna is about to hold its annual R&D day tonight and, for
the first time, reveal the status of their version of GalNAc-RNAi trigger
conjugates. To wit, when Dicerna
licensed LNP technology from Tekmira for their primary hyperoxaluria
development candidate, it concurrently announced that future development
candidates will be based on GalNAc conjugate technology.

For stock market investors, the big question is whether the
data suggest sufficient maturity and competitiveness compared to the more
famous GalNAc-siRNAs by Alnylam. If
Dicerna can show tonight robust and prolonged knockdowns in non-human primates,
e.g. in the form of an ~80% PCSK9 knockdown after 30 days with less than 10mg/kg, Dicerna could
be viewed as a great Alnylam catch-up investment. This is because such maturity would allow
Dicerna, which sports a market cap just 1/30 that of Alnylam, to rapidly expand
its liver-directed pipeline.

Scientifically, this should be possible although the
requirement for prior Dicer processing of Dicerna’s, but not Alnylam’s RNAi
triggers could impose limitations as to the extent of nucleic acid
modifications. It is a high degree of stability and consequently
modifications that has been key to Alnylam’s recent technology progress.

On the other hand, an unanticipated upside would be if Dicerna could reveal
advantages over Alnylam’s technology that are a direct reflection of it using a
slightly longer RNAi trigger.

Sunday, December 14, 2014

Talk is one thing, acting on it another. This has also been true for RNA Therapeutics
industry bellwethers ISIS Pharmaceuticals and Alnylam when they talked about their belief in the revolutionary nature of their technologies, but
their actions suggested they were plagued by self-doubts. Following continued
improvements in their platforms and a string of clinical successes (ISIS-ApoCIII,
ISIS-SMA, ISIS-FXI, ALN-TTR02, ALN-AT3 etc), the gloves are off as they strive
to achieve Genentech-type $50-100B biotech glory within a decade by
expanding the scope of their development programs and retain increasing
commercialization rights.

$50-100B is around the market cap that a few dominant players often achieve for a technology area that 'has made it'. In the case of ISIS Pharmaceuticals, however, I can foresee that, due to the currently wider choice of modalities and tissues amenable to single-strand antisense technology (incl. single-strand RNAi), full maturity could result in the
world’s largest company by market capitalization.

To get there, however, it is important for the
companies to have a strong believe in their own technologies and this in drug development means retaining more and more of the commercialization rights instead of giving away most
of the upside by early-stage out-licensing and partnering.

Alnylam- it’s all about the GalNAc (at least for now)

In the case of Alnylam, this shift has further been emphasized last week when
they introduced the STArs strategic initiative, expanding from the original
orphan genetic applications to developing medicines for more common illnesses
such as in the cardio-metabolic arena as well as some of the viral hepatites
(B,D, and E).

When Alnylam gave away the PCSK9 target to The Medicines
Company in early 2013- which parenthetically is making MDCO along with RGLS arguably the best 2015 RNA Therapeutics investment idea on
a risk:reward basis- the company was still unsure about its own position in
the pharmaceutical universe with a first-generation GalNAc delivery technology as its foundation which required large amounts of siRNAs and injection volumes.

Now, with remarkably potent and long-lasting versions of GalNAc-siRNAs, convenience and safety have improved so much that
RNAi has become highly competitive even for the very common cardio-metabolic
disorders such as type II diabetes and high LDL cholesterol. With that confidence, expect RNAi to shatter
some of the former domains of a long-time biotech darling it has long been living in the shadow of: the monoclonal antibody
(ALN-CC5 and ALN-PCSK9 being the first two examples of that).

ISIS- no end in sight

In the case of ISIS, this confidence shift was emphasized when they announced that instead of partnering away the lipid franchise as they
would have done before, they are now setting up a semi-independent
commercialization entity around their ApoCIII-, Apo little a-, and ANGPTL3-targeted drug candidates.

It was a confluence of factors that turned me from an ISIS
skeptic to an acolyte earlier this year. Along with first signs that ISIS was prepared to actually sell drugs themselves, in terms of scientific progress these factors should result in an exciting pipeline centered around targeting not 'only' the liver, but also the many severe neurodegenerative
diseases.

Add to this the ever expanding target space for and opportunities with antisense, it is difficult for me to see where all this should end as long as ISIS can 1) remain independent; 2) retain its
industry-leading position; and 3) the healthcare market can pay for its medicines. Time to dream BIG.

Wednesday, December 10, 2014

Earlier this week at the American Society of Hematology
meeting in San Francisco, Alnylam presented first multi-dose knockdown data in humans for
its second-generation GalNAc-siRNA conjugate technology (ESC-GalNAc). Accordingly, an almost 60% knockdown was
seen in the first (and so far only) patient dosed at 0.045 mg microgram per
kilogram ESC-GalNAc siRNA with the knockdown yet having to reach its nadir. Moreover, further knockdown benefits are
likely to accrue with dosing beyond 3 times weekly as was the
case in this study.

At these low doses, no remarkable adverse events were
reported, including injection site reactions or increases in liver enzymes which were seen with first-generation GalNAc-siRNAs in humans at much higher doses.

Though the data from this phase I study of ALN-AT3 in hemophilia
patients is still early and there will be gene target-dependent differences in
knockdown potency, they do support Alnylam’s claim that second generation
GalNAc is indeed considerably, as much as 50x more potent than first-generation GalNAcs. Only last week I had speculated
that it may be more appropriate to estimate 2nd gen GalNAc to be ‘only' 5x more potent than 1st
gen GalNAcs.

I was wrong.

In non-human primates, ALN-AT3 had an ED90 of 0.5mg/kg with
weekly dosing. Based on the phase I data
thus far, I expect the corresponding ED90 dose in humans to be a ~ weekly 0.075mcg/kg 0.075mg/kgfor a ~7-fold
improvement in potency in humans versus non-human primates, a relative potency improvement that is not seen for first-generation GalNAcs. Add to this the inherent 5x improved intra-species potency of
second- versus first-gen GalNAc (Nair et al 2014), it is indeed
possible that ESC-GalNAc enjoy an up to 50x improved potency advantage.

In other words, it should be possible to now achieve highly
potent knockdown with a once-monthly dosing regime and sub-1 ml subcutaneous injection
volumes.

The value of this for the ALN-AT3 program, which harnesses a
unique mechanism in an otherwise crowded hemophilia field which in general is
moving towards less frequent dosing/infusion regimens and less immunogenic molecules,
remains to be seen. The slow enrolment
pace of the phase I trial, ~5 hemophilia patients enrolled in 6 months, gives
cause for commercial concern.

The competition

While the improved potency is great for Alnylam, the gene
knockdown competition is unlikely to yield the liver to Alnylam. Highly potent knockdowns are possible with
other platforms by Arrowhead, ISIS, Tekmira, and possibly Dicerna, too. Beyond route
of administration [subQ for Alnylam GalNAc, ISIS (GalNAc-) ASOs, Arrowhead’s
single molecule DPCs, and Dicerna GalNAc versus intravenous for Arrowhead’s
2-molecule DPCs and Tekmira’s SNALP LNPs], differentiation will come from
safety/tolerability and dosing frequencies.

Monday, December 8, 2014

Yesterday, ISIS Pharmaceuticals disclosed in-depth data from
their phase II anti-clotting study in about 300 patients undergoing total knee
arthroplasty (TKA). This took place at the American Society of Hematology (ASH) meeting
alongside a publication in the New England Journal of Medicine (Bueller et al. 2014). The data for the first time
provide striking evidence that it is possible to dissociate anti-clotting activity
from a commensurate increase in the risk of bleeding.

Accordingly, while the 200mg per week dose (moderate 59% FXI knockdown) achieved a rate of venous thromboembolism (VTE) similar to the enoxaparin standard-of-care comparator in the trial (27% and
30%, respectively), at the 300mg per week dose (much more robust 78% FXI knockdown) the VTE rate dropped by 7-fold to just 4%.

At the same time, bleeding risk remained the same, if not
better for ISIS-FXIRx vs enoxaparin: 3% bleeding events for both FXI cohorts vs 8% for enoxaparin, albeit this was not a statistically significant
difference.

In terms of safety and tolerability, ISIS-FXIRx resulted in
mild local skin reactions in 6.6% of the injections, but leading to no
discontinuations. Moreoever, no flu-like symptoms were recorded. This is a stark departure from ISIS’ legacy
drug mipomersen which suffered from frequent flu-like symptoms and injection site
reactions resulting in relatively frequent drug discontinuations.

Challenging the paradigm

Until now, it has been widely thought that
whenever you develop a new, more powerful anticoagulant, you will pay the price
of more bleeding. This has meant not
only much development money wasted, but also created important
market needs such as in patients which require anticoagulants with lower bleeding risks.

It is these markets, including patients with end-stage renal disease and atrial fibrillation, that ISIS Pharmaceuticals will address
first as it seeks a partner more familiar with the complexities of the anti-clotting
market.

What seems to underlie the surprising results is that with
Factor XI you are targeting the intrinsic branch of the clotting cascade which prevents the formation of large clots that may travel around the body often
with fatal consequences, but without impeding the ability to form small clots
when healing tissue damage following trauma caused by external factors.

By contrast, conventional anticoagulants such as enoxaparin
(a heparin derivative), Factor Xa and thrombin inhibitors interfere with both
processes.

Challenging the establishment

The strategy of addressing niches of high
unmet need in the anticlotting market first is not only explained by potentially faster orphan-type
development timelines, but also by the fact that by presenting such disruptive
data in a multi-billion market, ISIS can be expected to encounter stiff
resistance from the anti-clotting establishment.
This refers not only to competing pharmaceutical companies, but also
their associated key opinion leaders from academia that enjoy a
gate-keeper function partly due to the regulators commonly seeking their
advice.

So given that the efficacy results are undoubtedly impressive,
expect over the coming days, months, if not years to hear the message that the ISIS-FXIRx data ‘might’ be a proof-of-principle for dissociating clotting from bleeding for
anticoagulant therapy, but that this 300-patient study needs to be replicated
in a larger population and that there are ‘concerns’ around the tolerability and
convenience of ISIS-FXIRx, all the while the same groups are busy catching up
developing antibody- and small molecule-based versions of anti-Factor XI drugs.

Wednesday, December 3, 2014

The GalNAc-RNAi trigger strategy pioneered by Alnylam and
Arrowhead Research has opened up new opportunities for RNAi Therapeutics,
partly due to the fact that they may be administered subcutaneously (note: for Arrowhead that means the single
molecule DPC which is not yet in clinical development). Although the first such product candidate,
ALN-TTRsc, looks like it could be a decent drug for a severe disease such as TTR amyloidosis,
there is room for improvement both in terms of efficacy (--> injection volumes) and tolerability/safety (liver enzyme elevations, skin reactions).

It is therefore no surprise that Alnylam keeps stressing the
fact that it has improved upon ALN-TTRsc, now referring to the original GalNAc chemistry
as ‘standard chemistry’ (STC) and the improved version as ‘enhanced
stabilization chemistry’ (ESC). By
inter- and extrapolating data from various model systems and for various target genes, the
company has come up with the notion that ESC ‘has the potential’ to be around 50x more potent than STC (IR
departments know that investors will be blind to qualifiers like ‘has
the potential’).

I love it when maths meets biology.

These numbers games, of course, make little pharmacological sense, mostly due to the fact that the same delivery chemistry
can result in disparate knockdown efficacies just due to sequence and target gene differences. In addition, concluding anything about a dose response from a ~25% knockdown in a single-dose, single dose level phase I study (--> ALN-AT3) is impossible. In RNAi, a 25% knockdown can be achieved with
homeopathic drug levels and does not inform at which drug concentrations more
robust >50% knockdowns will be observed.

Apparently, Alnylam is seeing it the same way and probably has received the same criticism from other sources. It has now provided on two recent occasions much more informative datasets on the relative potencies of
STC versus ESC.

At the Cantonese Nucleic Acids Forum (CNAF) in Guangzhou,
China, in early November, Dr. Manoharan revealed that if you turn the STC of ALN-TTRsc
into an ESC, the gain is a 5x in potency. Consistent with this 5x notion is the Nair et al. paper that published 2 days ago in
JACS where the same exercise for an siRNA sequence against the murine transthyretin gene resulted in the same 5x improved potency.

Of importance to the RNAi community, the enhanced metabolic stability
was achieved by the use of phosphorothioate bonds at the 5’ ends of both the
guide and passenger strands, while the 3’ ends are protected in both
generations by phosphorothioates in the overhang (guide strand) and the GalNAc
ligand (passenger strand), respectively.
I would not necessarily have predicted that phosphorothioates were tolerated at the guide 5’ end and this could be all the material difference there
is between STC and ESC.

All eyes are now on the ALN-AT3 phase I data presentation at
the upcoming ASH meeting next Monday (abstract here).
To wit, in part A of that study, Alnylam reported a ~25% mean peak
knockdown for the 0.03mg/kg starting dose in healthy volunteers earlier this year (single dose). Although there was no dose response data and
they had failed to reach the maximum allowable AT3 knockdown of 40%, part A was
deemed a success with the study proceeding into part B in hemophilia patients
for further dose escalation and repeat dosing. First data from that part is to be revealed.

Friday, November 28, 2014

Earlier this week, the scientist in me was shocked by the ~$700M
acquisition of Prosensa by orphan disease company BioMarin for its Duchenne Muscular Dystrophy splice modulation candidate drisapersen.
My initial surprise was due to drisapersen being a drug that had not long ago gloriously failed a pivotal phase III trial, not least due to a questionable therapeutic index. All this is not very surprising since drisapersen is based on antiquated oligonucleotide chemistry (2’-O-methyl phosphorothioate).

After a moment of reflection though, I have come to take a more positive view of the deal as it is actually a very bullish sign of the interest by the
wider pharmaceutical industry in RNA Therapeutics. This is because BioMarin is taking the gamble here that it will be able to argue its way to approval by
pointing towards drisapersen having shown evidence that it can positively influence the splicing of
the disease-causing gene, dystrophin. So
even if your clinical evidence of efficacy is anecdotal at best, it is
difficult to argue with the notion that such evidence in combination with being
able to positively impact the root cause of a disease is not an important
step in treating an orphan disease of very high unmet medical need.

It should be clear to everybody that if drisapersen can get marketing approval, other exon 51 splice skippers with superior chemistries
(many of which are pushing forward in development) will eventually replace it as
best-in-class. I would be surprised if BioMarin
did not see it the same way, but similar to Roche acquiring Intermune for $8.3B for its IPF
drug which had marginal efficacy in a severe disease of high unmet need, the rationale seems to be that being first-to-market in such pioneer indications will allow you to
build a strong franchises in those areas.

It will be interesting to see whether this strategy pans out and
BioMarin can
get accelerated approval in 2015-6 based on some seemingly positive phase IIresults in combination with the dystrophin biomarker evidence.

Regardless, the $700M valuation and ~60% premium of the offer to its
stock price is a powerful reminder that part of the reason what makes RNA
Therapeutics so compelling is that it often allows you to drill down to the root cause of a disease. From a commercial perspective this is particularly valuable in an environment favoring drugs for severe orphan
diseases.

Monday, November 24, 2014

As a veteran armchair RNAi Therapeutics strategist, I am
frequently frustrated at the inflexibility of companies in the face of rapidly moving competitive and drug development environments. The worst offenders are those with management and Boards that view their positions as entitlements and could not care less about the science and acknowledge the flaws of their technology.

Often related to this, another common violation is a failure to cut your losses on an obviously
failed development program at the cost of the platform, a strategy though that sometimes works if you can find a greater fool (the ~$700M acquisition of Prosensa by Biomarin yesterday falls into that category).

Tekmira, too, has been at risk of suffering from such inflexibility in light of an industry-wide shift from nanoparticle-based to small conjugate-based delivery. This does not mean that nanoparticle-based delivery will not have an important role to play in the future of RNA(i) Therapeutics, but that you have to realize your relative strengths in a highly competitive space. In addition, Tekmira has been slow to realize the shifting regulatory and payor landscape making biomarker-focused orphan drug development in genetically defined patient populations highly attractive.

Having listened to the Tekmira Analyst Day last Friday, I
was therefore quite pleased that not only is Tekmira catching up by beginning to realize that it is running a business and not a scientific think tank, it can even be considered to take on a strategic leadership role in at least two regards:

At the Analyst Day, Tekmira re-iterated that it will put a multivalent HBV formulation into the clinic that will contain three RNAi triggers. In addition to ensuring that most patients
thus become a match for the therapy, just as the two-trigger ARC520 by Arrowhead
Research had been geared towards, Tekmira also wants multi-targeting to address viral
resistance of the kind it observed in the woodchuck model of HBV.

From that perspective, the intravenously
administered TKM-HBV is preferable to single molecule approaches by Alnylam and
ISIS Pharmaceuticals which are both administered subcutaneously.

Tekmira does not limit multivalent RNA Therapeutics to viral applications such as in their HBV and Ebola programs, it will also apply the concept outside that space such as in its
hypertriglyceridemia program where it is considering dual-targeting formulations
with ApoCIII, ANGPTL3, and DGAT2 as candidate targets.

Equally or even more intriguing, in the Q&A session it was hinted that other therapeutic strategies that the company is considering may not merely involve multiple payloads of the same type, but even payloads from different categories such as an mRNA and an
RNAi trigger. Obviously, such combinations could open up entirely new therapeutic strategies (e.g. mRNA-RNAi combos for alpha-1 antitrypsin),
or maximize potency (e.g. RNAi trigger-RNaseH ASO for HBV).

Scientifically, I see no reason why single molecule technologies such as GalNAc-siRNAs should not be amenable to certain (but not all, e.g. mRNA) multivalent approaches. Culturally, however, multi-valency takes away from the single molecule simplicity that
the pharmaceutical industry apparently loves, ideally in pill form. From a regulatory point of view, it seems to
be the case that nanoparticle-encapsulated RNAi products are seen as just one
drug no matter how many RNAi triggers it contains, and it remains to be seen what the
regulatory thinking would be when combining multiple single RNAi triggers (I can imagine Alnylam trying to combine their HBV mRNA-targeting GalNAc-siRNA with its PD-L1 GalNAc-siRNA).

In some ways, ARC520 (which is not a nanoparticle) strongly indicates that multi-targeting is not
an insurmountable challenge for the non-nanoparticle approaches, so that
regulatory advantage may not exist in the future.

Nevertheless, my prediction is that multi-targeting will be
mostly practiced in the nanoparticle and not the conjugate sector of RNAi
Therapeutics and nanoparticle-based companies ought to consider multi-targeting
almost a Must when there is direct conjugate delivery competition.

Although Tekmira is the most visible RNAi company for
multi-targeting, it should be added that multi-targeting has been the motto for
US-China-based Sirnaomics from the get-go in 2007.

2.Testing Multiple Delivery Technologies in
Parallel

The RNAi Therapeutics field is both blessed and plagued by the rapid progress in refining particular delivery platforms. Tekmira has already arrived at the 4th generation of SNALP LNPs while Alnylam is now talking about GalNAcs with standard and enhanced chemistries. With a multitude of preclinically validated alternatives, it is often difficult to determine which one
should be prioritized for human development.

This can lead to protracted development timelines when a
first formulation yields unsatisfactory results in the clinic and the
payload has to be re-formulated into a new delivery chemistry. Especially in competitive environments this can be fatal. And even if you were
somewhat satisfied with the initial results, chances are that you left a lot of
money on the table by not finding out about the performance of other formulations in humans.

Needless to say, having multiple candidates for a target is
not a unique challenge in the pharmaceutical industry and if money were not an
issue, we would see a lot more parallel development programs. However, RNAi and related delivery is unique as
the investment can be amortized across the platform.

Moreover, in practical terms, RNAi offers a
number of opportunities to directly and accurately measure target engagement and thereby assess the impact of changing the formulation. This is one of the reasons why the early RNAi programs targeting genes in the liver involve targets which can be found in the blood. For other modalities (e.g. microRNA inhibition in the RNA
Therapeutics field), what you measure in your blood sample or other biopsies
may differ significantly from what is actually going on in the body.

For these reasons, namely to speed up time-to-market in a
competitive market and to inform which delivery formulations should be used
with other LNP-enabled candidates, Tekmira announced that it is about to put
two formulations of TKM-HBV in the clinic that will only differ in their
delivery chemistry while using the identical (3) RNAi triggers.

Tekmira investors are not seeing double: the company is becoming a modern drug developer.

Monday, November 17, 2014

In early 2013, Solstice Biologics was the first most notable
RNAi platform start-up after the industry had gone through the 2008-2011 RNAi Valley of Death. The idea was to develop new single molecule RNAi triggers that would have better
pharmacologic attributes than the highly negatively charged small
double-stranded RNAs, as well as increased stability and reduced immunogenicity.

Today, a publication by the Dowdy group (Meade et al 2014), the academic
birthplace of the technology, was published in Nature Biotechnology revealing
for the first time more detailed insights into the fundamental approach.

Accordingly, the charge and stability issues have been
addressed by esterifying the sugar-phosphate backbone with a biocleavable thioester,
turning the phosphate diester into a triester.
Despite some steric constraints due to the nature of the double helix,
the majority of phosphates could thus be triesterified thereby creating a more
or less neutral RNAi trigger molecule: siRNNs (small interfering ribonucleic neutrals).

Once in the cytoplasm of the target cell, the triesterified
RNAi triggers get converted by the ubiquitously expressed thioesterases into
canonical charged RNAi triggers which only then become competent for utilization by the
RNAi machinery.

Importantly, the molecules could be synthesized by methods
closely related to standard phosphoramidite-based synthesis using modified
phosphoramidites as the building blocks.
To this end, the Dowdy group and Solstice have created a library of
modified phosphoramidites, including those amenable to the conjugation to cell-targeting ligands and endosomal release functionalities.

The study validated the high stability and reduced
immunogenicity of the siRNNs and showed their increased binding affinity to plasma proteins such
as albumins. The latter is predicted to facilitate improved pharmacokinetics.

Unfortunately, the in vivo validation stopped at the stage of using GalNAcs as the
targeting ligand, because this attribute is predicted to be an advantage for
particularly the delivery outside the liver where we might not find receptors
with high uptake capacity similar to ASGPR on hepatocytes.

Another favorable attribute of the charge-neutral siRNNs, but which
remains to be demonstrated, is improved tissue penetration. Finally, it is possible that siRNNs have an
advantage in overcoming cell membranes as well which is consistent with the apparent
improved potency of GalNAc-siRNNs over standard siRNA-GalNAc conjugates (40 vs
55% knockdown in an experiment).

In many ways, siRNNs remind me of the self-delivering RNAi
trigger approach first pioneered by Dharmacon and later adopted by RXi
Pharmaceuticals. However, there are at
least two important differences: 1) self-delivering RNAi triggers still contain
negative charge; and 2) self-delivering RNAi triggers should be structurally
more flexible due to the shortened double-stranded region (~12 base-pairs vs 19
base-pairs) which, however, comes at the expense of impaired potency.

I greatly welcome this publication as it represents a
fundamentally differentiated approach to RNAi Therapeutics drug development and it
will be exciting to see where the Dowdy group and Solstice Biologics will take
this versatile platform for RNAi and potentially beyond.

Show me the non-human
primate data. Robust evidence of
gene knockdown in monkeys is a key requirement to gain confidence in a company’s
liposomal delivery claims. Dicerna has
never done that and yet been able to pull off an IPO and make claims about
clinical development timelines without actually being in possession of a realistic
delivery technology.

In retrospect, it is not surprising that they eventually had
to come hat in hand to the liposomal delivery powerhouse, aka Tekmira- after
claiming that its liposomal delivery technology (EnCore) was superior to
Tekmira’s… After all, Dicerna is under
pressure to get its first proper development candidate in the clinic for Primary
Hyperoxaluria Type I (PH1), especially after Alnylam had publicly announcedtheir intention to go after PH1, too.

According to the agreement announced today, Dicerna will use
Tekmira’s 3rd generation LNP technology and manufacturing to get
DCR-PH1 into the clinic sometime in 2015.
In return, Tekmira will get $2.5M upfront, $22M in potential development
milestones and single-digit royalties- in other words, nothing to write home
about other than the satisfaction that they were proven right scientifically.

You may interject that Dicerna already has a clinical program
using EnCore technology, DCR-MYC for cancer. Unfortunately, there are many ways to curing
cancer in mice and I am yet to be convinced that they have been primarily the
result of RNAi mechanism of action.

In summary, a moral victory for Tekmira, a deal that made
sense for Dicerna and which could and should have happened a long time
ago. In a final twist of irony, Dicerna has
given Tekmira a back-handed compliment in issuing another press release today where
it announces that future development programs will be based on Dicerna’s
conjugate delivery technology.

Now that makes
actually sense for a Dicer-substrate-based company. Expect Alnylam to increase its saber-rattling vis-a-vis Dicerna.

Friday, November 14, 2014

Alnylam this morning reported top-line results from a phase
II study of their first clinical candidate based on the GalNAc-siRNA conjugate
delivery technology, ALN-TTRsc for TTR amyloidosis. Accordingly,
average knockdowns of ~85% were seen in the 5mg/kg dose group, thus confirming
the robust potency at around the dose that the company plans to take forward in
later-stage studies.

Such potency, however, came
at the apparent expense of relatively frequent injection site reactions (23% of patients), with an additional skin reaction seen outside the area of injection. Moreover, there was a trend towards elevated liver enzymes, a marker of liver toxicity, including one that was adjudicated a serious adverse event (SAE;
~4x ULN deemed mild severity).

The efficacy data do not come as a surprise given that they
were largely in line with that seen in the phase I study a year ago, which
included the same dose group (5mg/kg) at the same dosing schedule (first 5x
daily, then weekly for 5 weeks). In both
cases average TTR reductions of ~85% were seen, with the difference being that this study involved
23 subjects at this dose (plus 3 subjects at 7.5mg/kg which was not further pursued for undisclosed reasons) while the phase I study involved only 3 comparable subjects.

The efficacy is thus in line with the intravenous ALN-TTR02
which utilizes Tekmira’s liposomal delivery technology and which so far has
been very well tolerated. Critics (aka LNP haters), however, are keen to point out the
use of (transient) immune suppression.
The efficacy of ALN-TTRsc is superior to the antisense compound by ISIS and GSK which
has shown 70% target gene knockdown in a short 4-week phase I study. Assuming maximal knockdown efficacy has not
been reached at this time-point, ISIS-TTRRx is likely to max out between 75 and
80%.

Similar to potency, the injection site reactions were not really a surprise given that in the phase I study this was the most common side
effect. What is new is that there was a
skin reaction that occurred outside the area of injection possibly indicating
systemic immune activation.

The liver enzyme elevations, however, were certainly
new. This could be related to histologic observations of granulations in the cytoplasm of hepatocytes, likely reflecting
storage sites of the fairly stable modified RNAi triggers.

My hope and expectation is that particularly the injection site reactions, but also liver enzyme elevations will
lessen with the lower doses enabled by the more effective second generation ESC GalNAc chemistry. Still, for ALN-TTRsc the safety
profile looks adequate for an indication like FAC (familial amyloidotic
cardiomyopathy), but 23 is still a small number to be sure.

Lastly, if I had to choose between
ALN-TTRsc, ISIS-TTRRx, and ALN-TTR02, I would go with ALN-TTR02 with the best
apparent risk:reward, regardless of whether it's an intravenous procedure or not.

Disclosure: Long ISIS Pharmaceuticals, no positions in Tekmira and Alnylam.

Monday, November 10, 2014

The upcoming phase I top-line data for ISIS-STAT3Rx in liver
cancer (HCC) to be presented at the upcoming EORTC-NCI-AACR triple meeting in Barcelona (Nov 18-21) will be an important test of the
potential utility of RNAseH antisense oligonucleotides (ASOs) incorporating
high-affinity chemistry in oncology.

Based on the body language by ISIS Pharmaceuticals* and last week's $7.5M milestone payment from partner AstraZeneca for progress on ISIS-STAT3Rx (aka AZD9150) , I am tempted to speculate on more than
just ‘encouraging’ results. On the other
hand, Regulus Therapeutics partner Sanofi at the Canton Nucleic Acid Forum (CNAF) also last week, noted the need
for formulating antisense oligonucleotides to get their anti-miR21 oncology candidate into liver cancer tissue. It is likely that they will be using liposomes for that (--> Tekmira?).

* I was surprised that
at the CNAF in Guangzhou,
China, Brett Monia from ISIS mentioned STAT3Rx and cancer right after gene
silencing in the liver as the next interesting application for ASOs- that is ahead of even the exciting CNS opportunity.

The discrepancy in body language may be explained by just
cultural differences (conservative, blasé Big Pharma versus risk-taking, enthusiastic biotech); it may also be a reflection of
different requirements for effective tissue concentrations with RNaseH versus
anti-microRNA modalities or different target requirements.
Whatever the reason, the Sanofi comments clearly support the notion
that getting naked, even phosphorothioated oligonucleotides into cancer tissues
is not as robust as with other tissues such as the liver and kidney.

I am therefore pleased that it is a Big Pharma, the last
place where I had expected that from, that is connecting the dots and is
considering delivery formulations, even the supposedly ‘toxic’ LNPs. The concept is that the nanoparticle would
facilitate a higher tumor concentration of the oligonucleotide, and once in the tumor interstitial space,
cellular delivery may be facilitated via two routes. Firstly, it may be traditional liposome-dependent cell uptake and cytosolic release. Alternatively, those LNPs that get stuck in
the interstitial space would spill the phosphorothioate oligo which may then diffuse further and get into the target cell by self-delivery.

The same concept, of course, applies not only to phosphorothioate ASOs, but also to self-delivering RNAi
triggers (+/- conjugation).

But why stop there? I propose that for cancer delivery, one should strongly consider and co-formulate
RNAi triggers and ASOs into a shared nanoparticle. They could target either the same gene, or
they could target different genes thus taking into account the desire for a
multi-pronged attack on cancer (-> resistance). In that
scenario you would benefit from the superior gene silencing efficacy of RNAi
triggers in those cells that they were able to reach, but then extent your reach with the help of the more agile, penetrative single-stranded antisense molecules.

As such, PS-ASOs have an advantage in addressing intra-tumor heterogeneity of the EPR effect which is a
well-recognized problem of nanoparticle delivery for cancer.

Another benefit of combining RNAi triggers with RNaseH ASOs
is that you could achieve additive gene silencing activity when going
after a shared target. For example, if
the RNaseH ASO and the RNAi trigger had both say a 70% knockdown activity on
their own in the nucleus and cytoplasm, respectively, the combined activity
would likely be ~90% which genetically could make a huge difference.

There is also a potency benefit, although more minor, when
going after different targets because at least in RNAi, the best you can hope
for when combining RNAi triggers against different targets is that they do not
interfere/compete with each other.

With solid cancer
data from both Tekmira (RNAi) and ISIS/AZ out over the coming weeks, we will
soon get a sense of whether the field has moved forward in oncology and what
the next steps ought to be.

Tuesday, November 4, 2014

Following yesterday's disclosure that yet another one of GSK’s target picks for
clinical development under their antisense options agreement with ISIS
Pharmaceuticals is an ocular one, I thought it worth highlighting that ocular
applications are regaining traction in oligonucleotide therapeutics in general. This follows a temporary lull in the area due
to setbacks with older generations of the technologies and funding issues for
the industry.

Aptamers still in the
lead

It may surprise you, but the eye is the one area in
oligonucleotide therapeutics where aptamers,
nucleic acids binding protein targets based on their shape not sequence (similar to antibodies),
are most advanced. Despite of the fact that the first
approved aptamer, Macugen, is considered a great disappointment as it lost out to the monoclonal
antibody competition in the VEGF market for wet AMD and DME, there are at least two new
development candidates that are poised to become blockbusters in the same
market: Fovista by Ophthotech targeting PDGF which has shown unprecedented activity in a phase II study in combination with anti-VEGF antibody Lucentis, and an
earlier-stage, but potentially superior VEGF/PDGF bispecific aptamer approach
by privately held SomaLogic.

It is now thought that the Macugen failure was due to it not
targeting the relevant VEGF isoforms. In
other words, it was a failure of target selection/biological insight, not a failure of the
technology. Aptamers should work well
for trapping extracellular proteins for ocular applications, because unlike their often rapid elimination
following systemic administration, they can be maintained at elevated
concentrations in the eye for sustained periods of time. Their
limitation, however, is in the number of targets available to them, similar to
monoclonal antibodies. Nevertheless, it
should be kept in mind that with even just 2 or 3 commercial successes in
a therapeutic area, a platform technology can be considered tremendously
valuable there.

Gene-regulatory
oligos catching up

Although ocular drug development has also been popular in both the antisense
and especially RNAi fields, previous technology generations were inadequate to effect robust
gene modulation, especially target gene knockdown. This holds true for 1st (à Vitravene) and 2nd
generation (cRaf inhibitor by iCo Therapeutics) antisense and the ‘naked’ RNAi
trigger folly of the early days of RNAi Therapeutics (à Acuity
Pharmaceuticals, Sylentis, Quark, and Sirna/Allergan to name just some of the
worst offenders of sound science).

The reason why antisense and RNAi are both staging a comeback in ophthalmology is due to the use of higher affinity chemistries (e.g. cET by ISIS) and self-delivering RNAi triggers, both in the form of (partially)
double-stranded (e.g. sd-rxRNAs by RXi Pharmaceuticals) and single-stranded RNAi
triggers (à
ISIS Pharmaceuticals). The increased
stability and lipophilicity combined with small molecular size should allow such an RNAi
approach to efficiently penetrate the vitreous of the eye following needle
injection and reach deep into the retina and other ocular structures. Similarly, what used to be a mediocre 40%
knockdown for ASOs could now be a genetically much more useful 70-80% knockdown
with gen2.5 RNaseH.

It is too early to tell whether RNaseH gen2.5, ssRNAi, or
sdrxRNAs will win out in the end. At
least in terms of timing, it will be as much a matter of investing in the
technologies as it is about their potential.
In particular, I am disappointed by the failure of RXi Pharmaceuticals
to recognize the need to further develop their sd-rxRNA chemistry.

So keep your eyes peeled as clinical results from the new
wave of gene-modulating Oligo Therapeutics will start to emerge in 2016 and beyond. It is possible that QPI-1007 by Quark Pharma
for ocular neuroprotection for NAION may be earlier than that, although the
chemical nature of this ‘2nd generation’ non-AtuRNAi trigger remains
unclear to me and therefore might be, or might not be a 'self-delivering' RNAi trigger. If not this one, the upcoming
clinical development of CTGF-targeting RXI-109 for retinal scarring by RXi
Pharmaceuticals should be an interesting one to follow.

Wednesday, October 22, 2014

This morning, Regulus Therapeutics greeted us with amazing results
from a phase I study of RG-101, an anti-microRNA 122 oligo for the treatment of HCV
infection. The results show that in the
exploratory HCV-infected patient subgroup, a single
dose of 2mg/kg of RG-101 resulted in a mean
viral load reduction of 4.1log on day 29. All responded with viral declines, with 6 and 3 of the 14 patients with viral levels below the level of
quantitation on days 29 and 57, respectively.

These results even
exceed my own wildest imaginations (as discussed here yesterday) and I’m amazed
how much this virus, in all patients, seems to have come to rely on this host-derived microRNA
for replication and/or genome stabilization.

It is not clear whether increasing the dose to 4mg/kg, the pre-planned upper dose
in the HCV-infected cohort for which dosing is ongoing will bring any additional benefit given that the
biomarker data (host genes targeted by miR-122) from the healthy volunteers
showed a plateau already at 2mg/kg, indicating the power of this GalNAc
chemistry approach. My guess is that the main benefit from a higher dose would be a decrease in response variability.

Interestingly, IL-28 status, frequently a predictor of
treatment success, did not influence the results, nor did HCV genotype seem to
have an impact (small numbers). This further supports that RG-101 could fill some
of the more attractive opportunities in the current HCV market.

Regarding safety, mild and transient injection site
reactions seemed most significant with no serious adverse events in the entire study, including the healthy volunteer cohorts (up to 8mg/kg). This is also consistent with data for Alnylam’sALN-TTRsc which uses a similar GalNAc chemistry and where multiple doses up to 10mg/kg had been tolerated, with injection site reactions, especially at 10mg/kg, being the
main safety finding.

So what’s it all
worth? The results position RG-101
to facilitate a 4-week HCV dosing regimen (compared to typically 8-12 weeks currently), potentially in combination with a
single direct-acting antiviral such as Olysio by Johnson&Johnson. One or two injections maximum. Great compliance, potentially pan-genotypic,
ideal for the busy practicing physician who does not have the time nor inclination to know the
ins and outs of each DAA.

In dollar terms, I’d like to think that with this drug profile,
this overlooked compound and company are worth as much as what Merck recently paid for HCV drug developer Idenix: $3.85B. The market valuation of Regulus
before the news: $300M. Needlessly to say that I'm long the stock.

PS: GSK once had rights to a precursor compound of RG-101
which it did not exercise. Importantly,
at the time, Regulus’ anti-miR122 compound was not GalNAc-enabled. This would have necessitated much more
frequent dosing and higher dosages and resulted in less potent and more protracted viral
declines, i.e. something that would not have been competitive in the current HCV marketplace. But as often the case with
Big Pharma and cutting-edge technology, today’s data clearly shows them
wrong. It has to be said though that GSK
more or less got out of HCV which also would have explained GSK’s decision RE
anti-miR122.

PPS: Congrats to Peter Sarnow and Catherine Jopling who in 2005 made the mind-boggling discovery that HCV relies on a microRNA for its replication. I hope they will be handsomely rewarded for it.

Tuesday, October 21, 2014

Regulus Therapeutics is on track to reveal phase I results
of its anti-HCV compound by the end of the year according to a presentation at last week's OTS. Although the phase I study
is largely a healthy volunteer dose-escalating safety study, it does involve a cohort of HCV
patients to assess the viral knockdown kinetics following a single dose of
anti-miR122 RG-101.

MicroRNA-122 is a small RNA host factor that had been identified to play an important role in HCV replication. As a therapeutic target it promises a low risk of viral resistance, pan-genotypic activity, and entirely novel mechanism of action making it suitable for combination therapy.

Based on the experience with an LNA-based competitor compound
by Santaris/Roche (Janssen et al. NEJM 2013), I predict a 2 to 3 log viral knockdown, with a 3 log viral
knockdown setting the scene for RG-101 as
a single shot in a 4-week treatment regimen in combination with
other oral direct-acting antiviral agents (DAAs). If viral reductions were on the low end of my
expectations, it may require 2 or 3 doses within 4 weeks for GalNAc,
cET-enhanced RG-101 to facilitate such a short treatment period which is considered a necessary attribute of future treatment regimens in an
increasingly competitive market.

However, the GalNAc conjugate in RG-101 is giving it a great
10-30x boost in potency, meaning that overall RG-101 should be 3-30x more potent
than miravirsen. It is because of this and considering
that RG-101 is given at 2 and 4mg/kg in the phase I trial in HCV patients, that I arrive at a predicted 2-3 log HCV reduction in the phase I study. This also makes the conservative assumption
that 3log viral reductions is all that an anti-miR122 treatment strategy may achieve based on the apparent plateauing of miravirsen at 5mg/kg. The 3 log prediction would require that a
single shot of RG-101 can already achieve super-therapeutic tissue levels of the oligo. This, however, cannot be assumed given that for non-ligand-targeted phosphorothioate antisense technology at least this would
normally require a multi-dose loading schedule.

But isn’t RG-101 late to the HCV game?

It’s long been thought that it’s game over for RG-101 given
the dynamics in the HCV markets. In
particular, the already approved and soon-to-be-approved all-oral DAAs which
typically achieve cures in >90% of patients in 8-12 weeks in well-supervised clinical trial settings, would make newer
agents like RG-101 seem outdated. On the
other hand, especially given cost pressures (~$100K per average treatment and ~4 million
infected in the US alone), the uptake of the new treatments has been relatively
slow with only 1-2% treated thus far (according to some of the analyst reports that I have read).
And even then, the sales have been spectacular: Sovaldi e.g. is on track
to become the most successful drug launch ever
being on track for more than $10 billion in sales in its first launch
year!!!

It is the cost pressures (pricing per pill, not per
cure) and improved adherence that make a shortened 4-week treatment period so desirable. A single or two subcutaneous injections in
the doctor’s office during routine check-ups where blood is taken anyway should
add to compliance. Holding the
subcutaneous route of administration of RG-101 against the drug is therefore
wrong in my opinion and the ‘all-oral’ notion, a misnomer really, has only been
so attractive because the former subcutaneous standard of care, interferon, was
so unpopular not because of the needle injections, but because of its side
effects.

So place your bets. I
believe RG-101 has value and will not only be superior to the Santaris/Roche
drug, but has pretty much caught up with it in development terms given that
miravirsen has only been tested with a DAA (telaprevir) that is already long outdated. As to the necessary Big Pharma/Biotech licensee, Johnson&Johnson tops my list.

Disclosure: Long
RGLS as an RNA Therapeutics stock waiting to be re-discovered with an
increasingly broad and clinical-stage pipeline and good financials. The RG-101 results should only be the trigger
for the re-discovery of this ~$300M market cap company.

Thursday, October 16, 2014

Yesterday, Tekmira Pharmaceuticals presented the long-anticipated RNAi candidate for the treatment of HBV infection at the Annual Oligonucleotide Therapeutics Society conference (click here for the corresponding slide deck). Accordingly, it was shown that TKM-HBV mediated solid knockdown of all HBV viral RNAs and proteins. This included data in the challenging (and costly) mouse model carrying humanized livers (comprised of a mixture of mouse and human liver cells) competent of supporting the full HBV viral life-cycle.

In these mouse models, repeat doses of 0.3mg/kg resulted in ~90% reductions of both the critical HBV surface antigen (HBsAg) and viral DNA. This may be an underestimate of the true potency of TKM-HBV as suggested by data targeting the human apoB gene in this model. These suggested (although not proved) that it is much more difficult to achieve potent knockdowns of genes expressed in the human liver cells as compared to genes expressed in the neighbouring mouse cells of the same liver: around 10x the amount of RNAi trigger was required to achieve comparable knockdowns for the human ApoB gene relative to the mouse ApoB gene.

Based on these results, I expect an approx. ~85% knockdown of HBsAg in single-dose studies at doses that I conservatively expect to be very well tolerated (~0.2mg/kg). As indicated by the recent clinical results with ALN-TTR02 and chimpanzee studies by Alnylam/Merck, both of which involved Tekmira's SNALP LNP delivery technology, these knockdown numbers are likely to improve with more prolonged repeat administration.

In case that Tekmira is able to safely dose escalate to higher dosages, say 0.5mg/kg, significantly more potent knockdowns can be expected. One ought to, however, keep in mind that such higher doses are not necessarily supported by the clinical history of SNALP LNP which indicates that innate immune stimulations could become an issue around 0.3mg/kg. On the other hand, the otherwise conservative Tekmira management has been surprisingly optimistic as to 3rd gen SNALP LNP-enabled TKM-HBV being devoid of innate immunostimulatory activity.

Comparison with Arrowhead's ARC520

The results support the notion that Tekmira's HBV candidate will be more potent than Arrowhead's competing HBV candidate, ARC520. However, there are many uncertainties in making such a prediction, most importantly the dose levels found to be safe and well tolerated in the clinical studies. To wit, ARC520 is still dose-escalating and so far has exhibited a very good safety profile meaning that 90% (1log)-type knockdowns are well within reach, especially with repeat dosing.

Beyond potency, it should be noted that TKM-HBV comprises of 3 different RNAi triggers, both to cover the vast majority of viral sequence variation and to minimize the potential of breeding drug resistance. To my surprise, such resistance mutations were observed in a woodchuck model that Tekmira conducted together with HBV powerhouse Bristol Myers Squibbs.

Oh, BMS? You can bet that should RNAi Therapeutics be able to meaningfully increase HBV cure rates from the low bar set by current standard of care (~15% with ill-tolerated immune stimulants), not only will BMS, but also the likes of Gilead be very interested to swoop in to pick up one or both of these compounds and/or companies.

An IND filing for TKM-HBV is on track for year-end 2014 with first drug administrations in early 2015.

Wednesday, October 15, 2014

On Monday, Alnylam revealed an update on their lead ALN-TTR02 drug candidate for the treatment of the FAP form of TTR amyloidosis. Given that this could be the first commercially meaningful RNAi Therapeutics to hit the market, a lot of attention is being paid to its progress in the clinic. Success and failure of this program are expected to have widespread repercussions for the RNAi, if not Oligonucleotide Therapeutics field.

Importantly, the data from the phase II open-label extension study provided strong evidence that the underlying SNALP LNP delivery technology, licensed from Tekmira Pharmaceuticals, is safe and well tolerated with 19 of the 27 patients involved having now received ALN-TTR02 once every 3 weeks for at least 6 months. After 282 doses administered, no drug-related serious adverse events were seen with infusion-related issues as expected the main source of adverse events. Notwithstanding the 8 mild flushing events and infusion reactions, there have been no drop-outs in the study so far.

On the efficacy side, ALN-TTR02 continued to produce robust sustained 80-90% knockdowns with a trend towards increased knockdown efficacy with prolonged dosing. This knockdown certainly puts ALN-TTR02 ahead of the competitor antisense drug from ISIS and GSK (ISIS-TTRRx) which is expected to be in the 70% range, but is probably ahead in terms of patient enrolment in their pivotal study.

The results presented at the ANA conference had been widely anticipated because it was the first time that Alnylam revealed measures of therapeutic efficacy beyond the gene knockdown. Accordingly, at the 6-month time-point patients treated with ALN-TTR02 exhibited less neurological declines as would have been expected from the Natural History of the disease. Unfortunately, in the absence of hard biomarker evidence indicating improved neurological and, for a subset of patients, cardiac functions, the apparent improvement in the well-being of the patients (mNIS+7) could easily be attributed to the open-label nature and the relatively early time-point of the study.

Therefore, despite of the fact that shares in Alnylam increased 20% on the results and the provider of the delivery technology, Tekmira, barely budged on the news, the most important take-home from the results was that SNALP LNP delivery technology and indeed extended robust RNAi has a remarkably good safety profile.

Monday, October 13, 2014

Last week at World Muscle, ISIS Pharmaceuticals provided an update on their phase II study results for ISIS-SMNRx for the infant- and child-onset forms of spinal muscular atrophy (SMA). Importantly, biomarker and biodistribution results were reported that clearly showed that ISIS-SMNRx is doing exactly at what it was designed to do, namely meaningfully increase target gene expression in the central nervous system (CNS).

The data not only greatly de-risk ISIS-SMNRx, but open up phosphorothioate-based antisense technology for a whole range of other, largely severe CNS-based diseases of high unmet need, including Huntington's disease, the spinal cerebellar ataxias, Alzheimer's, Parkinston's- you name it!

Biodistribution

Specifically, the data showed that despite only a focal, intrathecal infusion of the antisense drug into the lower spine, it readily distributed throughoutthe CNS up to the brain and at concentrations (10-30ug per gram tissue) that are strongly predicted to support both steric blocking and RNaseH antisense mechanism of actions in the CNS for 2' MOE chemistry. Further chemistry improvements such as cET are opening the therapeutic window even more so. What is more, these concentrations were maintained for months, thus further supporting the apparent therapeutic benefits seen in these open-label studies.

Note that the effective concentration for antisense mechanisms will differ according to target tissues; e.g. in the liver, largely due to competition from phagocytic Kupffer cells, the effective concentrations are 100ug/g and above with 2' MOE chemistry.

With the generous support of SMA families, the company was also able to look for the drug and the SMN protein in tissue sections from 3 deceased infants. These investigations showed that the phosphorothioate oligo had been taken up pretty much in every neuronal and non-neuronal cell types.

Such broad-based uptake may be quite important according to the opening keynote address of ISIS collaborator Don Cleveland last night at the annual OTS meeting in San Diego, given that expressions of disease-causing genes in various cell types, not just the neurons, seem to contribute to most neurodegenerative diseases.

Biomarker

In terms of drug action, the SMN protein was found to be re-expressed in the corresponding cells as intended for the splice-modulating approach of ISIS-SMNRx. This was shown by immunofluorescent analysis. Moreover, quantitative PCR showed that the expression of the intended full-length SMN2 mRNA was increased by 2 to 3-fold, consistent with the 2 to 3-fold increases in SMN2 proteins found from cerebrospinal fluid (CSF) samples in the child-onset studies.

No dose-limiting safety issues were seen and the intrathecal infusions which are predicted to be needed on a ~6 month-basis for many of the anticipated CNS-related antisense applications could be performed without having to resort to general anesthesia.

For SMA, genetically speaking all this essentially turns a type I infant-onset SMA baby into a less severe type II/III child, and a type II/III SMA child into a normal one, with the caveat that this benefit obviously only accrues from the time the drug is given which, unfortunately, may be too late for many type I SMA babies. I was e.g. somewhat disappointed that no apparent correlation was seen between onset of antisense administration and therapeutic outcomes in the infant study, although clearly the numbers may well have been too small (n=20). I am very hopeful, however, that those infants making it out to say 18 months and beyond with ISIS-SMNRx may see very good outcomes indeed.

Despite the caution, all this was accompanied by apparent therapeutic benefits in terms of survival and muscle strength. While highly intriguing, due to the open-label nature of the studies and the small patient numbers, it is not my intention to delve more into that aspect of the data and instead focus today on the truly mind-blowing pharmacodynamic data. These should provide hope for many patients and families with neurodegenerative diseases. If not, we might as well give up on rational drug development.

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